The broad goal of this work is to understand the genetic and molecular mechanisms of the control of cell division and differentiation during animal development. We will chiefly use C. elegans as a model system. Genetic and molecular analysis of C. elegans heterochronic genes will be performed to determine how this regulatory pathway controls the temporally coordinated expression of diverse developmental events in C. elegans larvae. Genetic and biochemical experiments will be performed to explore the molecular mechanisms of how lin-14 and lin-28, genes that play central roles in the control of diverse larval cell lineages, are regulated post-transcriptionally by the microRNA products of the lin-4 and let-7 family genes. There are at least 100 distinct microRNA genes in C. elegans, besides lin-4 and let-7, and the functions of these are largely unknown. We will use molecular and computational approaches to identify additional microRNA genes, and their regulatory targets, and we will employ genetic methods to determine the biological functions of all the C. elegans microRNA genes. C. elegans is an excellent system for the genetic analysis of microRNA function, and since many of the C. elegans microRNAs are conserved in mammals, understanding their roles in C. elegans should inform about the human health significance of microRNA-based regulatory circuits.